Lecture: Immune System and the Nervous System Flashcards
What is delirium?
• Clinical syndrome (a set of symptoms) of early brain or mental dysfunction
Precipitated by:
• medical illness
• substance intoxication/withdrawal
• medication side-effect
Can effect a patients thinking and result in reduced awareness of environment.
How is delirium diagnosed
Clinical diagnosis
Describe the three cardinal features of delirium
• Conscious state is altered: Stupor/ drowsiness vs hypervigilance/ agitation
• Cognitive impairment: Inattention, disorientation, global cognitive impairment Inability to focus
• Course: Fluctuating with an acute onset
Duration hours to days
What are three important differentials for delirium?
Differential diagnosis: important in distinguishing between a number of psychiatric
disorders as signs and symptoms are also present in
• Dementia
• Depressive disorders
• Schizophrenia
Describe typical symptoms of hyperactive delirium
Hyperactive
• psychomotor agitation, restlessness, anxiety, labile affect, verbal aggression, visual hallucinations
• Example: mania, psychosis but no previous history of psychiatric illness
Describe typical symptoms of hypoactive delirum
Hypoactive
• Somonlence, decreased attention span, withdrawn
• Example: withdrawn delirium – major depressive disorder. Can be misdiagnosed.
• MDD: cognitive symptoms but normal consciousness
What are some typical symptoms of delirium?
- Cognitive deficits (including attention, orientation, memory, visuoconstruction and executive functions)
- An acute onset
- Sleep/wake cycle disturbance (including cycle reversal)
- Abnormal affect (labile, irritable, agitation, restlessness, aggression, apathetic)
- Impairment of psychomotor behaviour
- Psychotic symptoms (hallucinations, fleeting delusions and thought disorder)
Describe alcohol tremens and common symptoms
- Severe alcohol withdrawal, with the following clinical features:
- Delirium
- Autonomic hyperactivity (diaphoresis, tachycardia, hypertension)
- Hypervigilance, agitation
- Tremors
- Often with hallucinations (esp. visual & tactile)
- Increased risk of alcohol withdrawal seizures & death
Describe some adverse effects delirium is associated with
Associated with the following:
• mortality
• risk of cognitive & functional decline
• hospital length of stay
• nursing care
• likelihood of needing residential placement
• post-operative recovery/rehabilitation
Predisposing factors to delirium?
Advanced age Sensory impairment Poly pharmacy Cognitive/functional impairment History of delirium Medications: - psychoactive drugs - anticholinergic drugs - alcohol abuse
Precipitating factors for delirium?
Drugs - polypharmacy - sedating drugs - anticholinergic drugs - substance intoxication or withdrawal Toxins Surgery Anaesthetics Critical Illnesses - neurological conditions (head trauma, tumor, cranial hypertension) - infections (respiratory, UTI) - hypoxia - metabolic/electrolyte disturbances - febrile illness - urinary retention/ constipation - pain
Outline the pathophysiology of delirium
Unclear
Functional imaging
• Generalised disruption of higher cortical function
Multiple pathways affected: • Neurotransmission (cholinergic deficiency, monoaminergic disturbances) • Physiological stress • Oxidative metabolism • Circadian rhythm (Sleep-wake cycle - maintenance of memory circuits) • Patient losses orientation • Limbic system • Immune system - neuroinflammation
What is psychosis?
A loss or break from reality. Clinical diagnosis NOT a disorder arising from abnormal brain functions.
• Characterised by fundamental distortions of thinking, perception and
emotional response
• Causes an individual to lose contact with reality during the active stages of
the syndrome– 4.5% of population
• Typically occurring late teens or early adulthood and can be recurring or
chronic
• Approx 1 in 100 people will experience psychosis in their lifetime and 1 in
4 will meet criteria for psychotic disorder
• A psychotic illness includes schizophrenia, bipolar disorder, schizoaffective
disorder and delusional disorder
Early warning signs of psychosis?
Depression, anxiety, feeling off, feeling as if thoughts have sped up or slowed down
What are the key features of psychosis?
Faculties of mental capacity that are altered during psychosis such as: Thoughts (delusions) Mood & Feelings Volition Cognition (memory, attention) Perceptions (Hallucinations)
These thoughts can lead to ALTERED BEHAVIOUR
Difference symptoms in primary and secondary psychosis?
No specific characteristic for either primary or secondary psychosis
Outline the diagnostic workup for psychosis
- Screen broadly
- Thorough history and examination
- Focus on a thorough neurological examination
- Mental state examination
- Bloods
- CBE, Glucose, Electrolytes, LFTs, BAC, CRP/ESR
- Neuroimagining
- CT scan or MRI
- CXR
- Exclude specifically if suggested
- Abnormal levels of TSH, TFT, vitamin B12 and folate, Syphilis/ HIV serology, FTA-Abs
- Investigate further as clinically indicated
- Electroencephalogram (EEG within a few weeks of presentation)
- Chest radiography, lumbar puncture, blood and urine cultures, arterial blood gases
- Serum cortisol levels
- Toxin search
- Drug levels eg urine drug screen
- Genetic testing
Main differentiating factors between Delirium and Psychosis
Pattern/course is more stable in p and fluctuating in d
Attention is delusion in p and disordered in d
Cognition is selectively impaired in p and disordered in d
Diagnostic criteria for Schizophrenia?
A. Two or more of the following, each
present for 1 month (or less if
successfully treated). At least one of
these must be (1), (2), or (3):
- Delusions
- Hallucinations
- Disorganised Speech
- Grossly disorganised or catatonic behaviour
- Negative symptoms
B. Decline in one or more major areas of
functioning.
C. Continuous disturbance for at least 6 months. Exclusion of mood or schizoaffective disorders, substance, general medical condition, or pervasive developmental disorder.
positive symptoms of schizophrenia?
Psychotic (distortion of reality)
- Hallucinations
- Delusions
- Catatonia
negative symptoms of schizophrenia?
Negative (Deficit) Symptoms
- avolition (disinterest, ambivalence)
- anhedonia (reduced experience of pleasure)
- Apathy (social withdrawal)
- affective (emotional) blunting
- Alogia (poverty of speech)
disorganised symptoms of schizophrenia?
- Formal thought disorder (disorganised thoughts, manifested by disjointed speech)
- Disorganised behaviour and inappropriate affect (eg smiling when discussing a sad event)
- Bizzare behaviours
Neurocognitive symptoms of schizophrenia?
- Common
- (overlaps with negative symptoms)
- Poverty of thought content
- Affects frontal lobe tasks – executive functions
- Associated with impairment in work and social functioning
Aetiological factors of schizophrenia?
• Multidimensional with genetic and environmental factors interacting: GxE
Genetic causative factors
- 80% heritability estimate
- monozygotic twins 50% concordant for schizophrenia
Environmental causative factors
- Prenatal and perinatal stressors
- Infectious agents
- Childhood and adulthood trauma
- Substance use
• Associations vary between person to person – heterogeneity
• Associated range of structural and functional brain abnormalities
• Variable longitudinal course – 40% having significant long term disability
Prevalence of schizophrenia
1 in 100
How is schizophrenia treated?
antipsychotics. Antagonise mono adrenergic pathways. Reduce hypersensitivity to dopamine.
What percentage of patients are resistant to antipsychotic treatment for schizophrenia?
- Treatment resistance:
- Up to 1/3 of patients fail to respond to antipsychotic medication
e. g. ( no effect on cognition) - After 2 failed trials (4-8 wks each), clozapine is indicated
- Severe refractory cases; ECT is an option
Side effects of antipsychotics?
- Common anti-psychotic side effects:
- Metabolic syndrome
- Sexual dysfuction
- Prolactin elevation
- QTc prolongation
- Extrapyramidal side effects
Empirical evidence for inflammation associated depression
- Elevated immune signalling mediators
• elevated levels of circulating granulocytes, monocytes and acute phase proteins, immune signalling molecules such as CRP, IL_1b, IL_6, TNFa compared to healthy controls and pronounced
in suicide attemptees .
• Also chemokines, prostaglandins, adhesion molecules. - Immune stimulating therapies
• 30-40% non-depressed melanoma/cancer or hepatitis C patients receiving immune stimulating IL_2 or IFNa develop depression (Denicoff 1987, Renault
1987) associated with increased IL_6 (Raison 2009) - Exogenous administration of immune signalling mediators
• Conversely experimental healthy animals demonstrate sickness behaviour post exogenous administration of IL_1b or TNFa - Anti-depressants
• Certain classes of anti-depressants exert anti-inflammatory effects (Hannestad 2011)
• eg selective serotonin reuptake inhibitors (SSRIs) can block effects of inflammatory cytokines on the
brain - Anti-inflammatories
• Conversely certain anti-inflammatories exert anti-depressive effects eg treatment with anti-TNFa antagonist (Infliximab) or aspirin in combination with minocycline
(Savitz 2013) - Gene association
• GWAS studies show links between certain gene variants (Caspi and mood disorders this means
differential gene expression between people with depression and those without (Savitz 2012) as are
abnormal alleles of IL_1b and TNF genes in treatment resistant MDD patients (Ma Li Wong 2008) - Epidemiological association
• an epidemiological association exists between MDD and disorders with an inflammatory or autoimmune
component such as MS, type 2 diabetes (Nouwen 2010) or cardiovascular disease (Van der Kooy 2007)
Evidence for Neuroinflammation as underlying
cause for pathophysiology of schizophrenia
Increased number of circulating monocytes
– enhanced gene expression of immune genes
Elevated monocyte/macrophage related pro inflammatory cytokines in CSF and periphery plasma/serum: IL-1, IL-6, TNFa, CRP
• Antipsychotic effects by anti-inflammatory drugs such
as NSAIDs and minocycline
• Microglial activation revealed by PET scans/ histopathology in brains from SCZ patients
